management options stage wise metastatic colon cancer targetted therapy

1. MANAGEMENT OF COLON CANCERS
Presented by: Dr. Isha Jaiswal
Guided by :Prof Kamal Sahni
Date :16th October 2015

2. TOPICS
• Management options
• Stage wise management
• Follow up
• Treatment of metastatic colon cancer

3. Management depends on
Tumor related
• Stage
• Location
Presentation
• elective
• emergency
Patient related
• Age
• Performance status
• Medical comorbidities
Molecular markers
Multimodality treatment
• Surgery
• Chemotherapy
• Radiotherapy
• Targeted therapy
Treatment options

4. SURGERY
Colectomy: principal treatment of Ca colon
Intention
 Curative
 palliative
 Accurate disease staging
 Guides adjuvant treatment
Indication
 Stage 1 -3
 Resectable stage 4

5. Aim of surgery
R0 resection considered curative
wide resection of involved colon segment +lymphatic + mesocolon +enblock resection of neighbouring
organs with adequate margin f/b reconstituting bowel continuity
 margin ~5 cm of normal bowel proximal and distal to tumor considered adequate
 Minimum of 12 L.N removed ,suspicious LNs out side field of resection removed or biopsied
 positive LN left behind considered R2 resection.
Inspect abdomen viscera,peritoneum,non localized lymph nodes for mets
Guidelines 2000 for colon and rectal cancer surgery. J Natl Cancer Inst 2001; 93:583.

6. TYPES OF COLECTOMY: anatomic resection
• Right/left Hemicolectomy:
• Extended Right/left Hemicolectomy
• Transverse colectomy
• Segmental resection
• Total Abdominal Colectomy: UC, FAP Syndrome

7. Extent of colectomy
dictated by the size and location of lesions, vascular and lymphatic supply.

9. Laparoscopic-assisted colectomy
may be considered based upon the following criteria:
• experience surgeon performing laparoscopically assisted colorectal operations.
• no locally advanced disease.
• not indicated for acute bowel obstruction or perforation.
NCCN 2015

10. Laparoscopic vs. Open colectomy
Randomized/non randomized prospective study data suggest no difference in oncologic
outcome in open vs. laparoscopic resection (1-4)
1. prospective random assignment trial conducted by Clinical Outcomes of Surgical Therapy (COST) Study Group A comparison of laparoscopically assisted and open colectomy for
colon cancer. N Engl J Med2004;350(20):2050–2059.
2. Fleshman J, et al. Laparoscopic colectomy for cancer is not inferior to open surgery based on 5-year data from the COST Study Group trial. Ann Surg2007;246(4):655–662; discussion
662–664.
3. Bonjer HJ, et al. Laparoscopically assisted vs open colectomy for colon cancer: a meta-analysis. Arch Surg 2007;142(3):298–303.
4. Jackson TD, et al. Laparoscopic versus open resection for colorectal cancer: a metaanalysis of oncologic outcomes. J Am Coll Surg 2007;204(3):439–446
Advantages:
• Improved visualization of visceral structure
• Better abdominal exploration
• Increased no. of lymph node dissected
• Small incision
• Early return of bowel function
• Better recovery
• Less hospital stay
Disadvantages:
Concern regarding
• inadequacy of resection margin
• Inadequacy in L.N sampling
• seeding of port sites
• Cost

11. Pathologic report
following parameters should be reported:
 Depth
 Number of L.N evaluated
 Number of L.N positive
 Status of margin: proximal, distal, and radial
 Grade
 LVI
 PNI
 Extranodal tumor deposits
College of American Pathologists Consensus Statement
NCCN 2015

12. Results of surgical resection
• Resection results in excellent cure rates for lesions limited to the
bowel wall with negative nodes (T1-T2 N0)
• average 5-year survival, 97% for T1 N0; 85% -90% for T2 N0
• With a single high-risk feature of extension beyond the colonic wall
(T3–4 N0) or involved nodes (T0–2 N+), 5-year survival with
surgery falls to 65% to 75%, and adjuvant treatment is often
indicated.
• When both high-risk features (T3–4 N+), 5-year survival with
surgery alone drops to approximately 50% (T3 N+) and 35% (T4
N+), and adjuvant treatment is recommended.
Stage Mean 5 yr
survival
(%)
T1N0 97
T2N0 85-90
T3N0 78
T2N+ 74
T4N0 63
T3N+ 48
T4N+ 35

13. ADJUVANT THERAPY
BASIS
• Despite curative surgery many patients suffer tumor recurrence leading to
cancer related death
• Therefore there is a need of adjuvant therapy to improve DFS and OS
• Adjuvant therapy is indicated in T3-T4 & N+ disease (stage II & III)

14. Stage I
• No adjuvant treatment
Stage II
• Role of adjuvant chemotherapy unclear for stage II
 STAGE IIA:T3N0M0
 STAGE IIB:T4aN0MO
 STAGE IIC T4b N0M0
• Risk estimation

15. Who Needs Adjuvant Therapy in stage II?
Indicated
pT4
Grade 3-4
LVI +
PNI +
<12 L.N examined
indeterminate, close or + margin
obstruction, perforation

16. Stage II
High Risk IIA & Stage IIB,IIC
• FOLFOX
• Cape-Ox
• flox
• Capecitabine
• 5FU + leucovorin.
Low Risk IIA
• Observation
• clinical trial.
• Capecitabine
• 5FU + leucovorin.

17. Stage III
Role of adjuvant chemotherapy established
Preferred
• FOLFOX
• CapeOx
Other option
• Flox
• Capecitabine
• 5FU plus leucovorin.

18. Adjuvant Chemotherapy
In Resected Colon Cancer

20. Evolution of chemotherapy regimen for Ca Colon
1. 5FU + Levamisole
2. 5FU + Leucovorin
3. oral 5 FU analogue
4. Addition of oxaliplatin to 5FU/LV
5. Addition of irinotecan to 5FU/LV
6. Capecitabine + oxaliplatin:
7. Monoclonal Antibodies:

21. 1990 1993 1995 2005 2006 2007 2009 2011 2012
Pooled analysis
High dose bolus
5FU/LV vs. obs.
Bolus
5FU+Levamisole vs.
observation
Bolus 5FU+LV vs MOF
Xeloda-ACT
similar OS/DFS less toxicity to Mayo regimen
Tegafur
Irinotecan with 5FU/LV:
No significant benefit.
Cetuximab with
FOLFOX
Bevacizumab
with FOLFOX
Cape-OX vs
FU/LV
1. Mayo Clinic: monthly bolus 5FU D1-D5
+LDLV
2. Roswell: weekly bolus 5FU+ HDLV
3. 5- FU/levamisole,
4. 5-FU/LV/ levamisole.
Overall survival similar, toxicity different
Dec neutropenia & mucositis, Increased
diarrhoea with weekly regimen
infusion 5FU/LV vs bolus
(Mayo)
Bolus 5FU/LV vs. FLOX
Improve DFS
Oxalipl.with infusion
5FU/LV
improved DFS & OS

24. Some Important Trials

25. Between October 27, 1998 and January 16, 2001, 2,246 patients were enrolled
randomly assigned to receive infusion LV5FU2 or FOLFOX4 for 6 months.
1,123 pt. in each treatment arm
The primary end point was DFS.
Secondary end points were OS and safety.
Intention to treat analysis
median follow-up time of 81.9 months

26. CONSORT diagram
A:3 pt. assigned to FOLFOX4 arm but did not receive oxaliplatin. Therefore, these patients were considered in FOLFOX4 arm
for efficacy analysis and LV5FU2 arm for safety analysis.
B:1 pt. assigned to LV5FU2 arm received oxaliplatin. Therefore, this patient was considered in the LV5FU2 arm for efficacy
analysis and in FOLFOX4 arm for safety analysis.

27. In both groups,40% and 60%of patients had
stage II and stage III disease, respectively
The planned 12 cycles of CT received by 74.7%
and 86.5% of patients in FOLFOX4 and LV5FU2,
respectively.

29. After a median follow-up time of 81.9 months, the probabilities of surviving at 6 years
Six-year OS rates were 78.5% and 76.0% in the FOLFOX4 and LV5FU2 groups, respectively
6-year OS rates for patients with stage III disease were 72.9% and 68.7%, respectively
No difference in OS was seen in the stage II population.
II
III

30. After a median follow-up time of 73.5 months in the FOLFOX group and 73.4 months in theLV5FU2group
Results Five-year DFS rates were 73.3% and 67.4% in the FOLFOX4 and LV5FU2 groups, respectively
(hazard ratio [HR] = 0.80; 95% CI, 0.68 to 0.93; P = .003).

31. J Clin Oncol 2012

33.  multicenter, randomized trial between April 2003 and October 2004
 compared capecitabine plus oxaliplatin (XELOX) with bolus FU/LV as adjuvant therapy
for patients with stage III colon cancer.
 primary end point = DFS
 Secondary end points were OS, relapse-free survival (RFS), and safety.
 intention-to-treat analysis
 Follow-up is ongoing ,cut-off date for the primary analysis was April 30, 2009.
 median follow-up duration was 55 months for DFS and RFS, and 57 months for OS

34. TREATMENT
1:XELOX (oxaliplatin 130 mg/m2
on day 1 plus capecitabine 1,000 mg/m2 twice daily on days 1
to 14 every 3 weeks for 24
weeks)
2: bolus FU/FA adjuvant regimen
(Mayo Clinic for 24 weeks
or Roswell Park for 32 weeks).
Overall,69%of pts in XELOX grp and 85% of pts
in the FU/FA grp (MC, 87%; RP, 79%) completed
the planned number of cycles.
Median relative dose intensities of capecitabine
and oxaliplatin were 78% and 84%, respectively.
For FU/FA MCand RP regimens, median relative
5FU dose intensities were 86% and 82%,
respectively
safety population was defined as patients who underwent random
assignment and received at least 1 dose of study medication

35. • addition of oxaliplatin to oral capecitabine improves DFS & RFS in
patients with stage III colon cancer.
• Treatment-related grade 3/4 adverse events were 55% in XELOX group
and 47% in FU/FA group (P<.05)
• additional treatment option for patients with stage III disease.

36. Conclusion:
Adjuvant therapy in stage III colon cancer

37.  Addition of oxaliplatin increased benefit :
i. FOLFOX is superior to5FU/LV therapy in stage III increased DFS & OS
ii. benefit for the addition of oxaliplatin to 5-FU/leucovorin in patients ≥ 70 not been
proven
iii. survival benefit has not been demonstrated in stage II colon cancer.
 Indicated in stage III & High risk stage II
 FOLFOX or CapeOx are preferred regimen in stage III colon cancer
 Capecitabine/oxaliplatin is superior to bolus 5-FU/ leucovorin for stage III colon cancer.
 Capecitabine equally effective to bolus 5-FU/LV

38. Among the various 5FU/LV regimen
• Schedule of 5-FU/LV administration does not affect efficacy, but toxicities may be
different
i. Mayo Clinic monthly regimen - more commonly associated with leucopenia and
stomatitis
ii. Roswell Park weekly regimen - more commonly associated with diarrhea
iii. Infusional 5-FU/LV may have less toxicity vs. bolus
• Irinotecan no benefit the adjuvant setting
• No targeted agents are approved for use in the adjuvant setting

39. Adjuvant Radiation therapy in colon cancer
Aim:
• tumor bed irradiation to decrease local failure.
• should be delivered in a highly conformal manner.

40. Rationale
local failure in colon cancer depends on stage & location
• anatomic constraints on radial resection margins,
• tumors adherent/ invading adjacent structures increases risk of LF
 LF high in ascending/descending colon :
• anatomically immobile,” limits wide surgical resection
LF less in mid-sigmoid and mid-transverse colon:
• relatively “mobile,” with a wide mesentery, wide margins
LF rates for ceacal, hepatic/splenic flexure, proximal/distal sigmoid tumors are variable,
• depending on amount of mesentery present, tumor extension, and adequacy of radial margins.

41. INDICATIONS OF RT
Adjuvant tumor bed irradiation with concurrent 5-FU–based
chemotherapy should be considered for patients with tumors
• invading adjoining structures: T4
• where incomplete resection is performed
• those complicated by perforation or fistula
Perez & Brady's Principles and Practice of Radiation Oncology

42. Data evaluating the use of adjuvant radiation therapy in high-risk colon cancer
patients have largely been limited to single-institution retrospective analyses
• Massachusetts General Hospital (MGH),
• Mayo Clinic,
• University of Florida

43. • randomized, prospective phase III trial in high risk post op cases
• inclusion: complete resected pts with: 1) T4 (any site), or 2) T3N+ (of ascending or descending colon
only).
• Ineligible patients :incomplete resection, medical comorbidities, prior radiation/chemotherapy
• pts. were randomized to PORT with 5-FU/Levamisole or 5-FU/Levamisole alone.
• recommended dose: 45 Gy in 25 # over 5 weeks, optional 5.4 Gy boost.
• primary goal :to determine whether addition of RT to CT improve survival among high risk pts.
• secondary objectives :DFS, patterns of recurrence, and toxicity.
• study was closed in 1996 due to poor accrual (Initial goal:700 pts. Total accrual 222 patients between
1992-1996)

44. 222 patients were enrolled onto this study.
 34 patients were ineligible (Table 1),
 one patient withdrew before receiving any
treatment
 remaining 187 patients :subject of primary
analyses

45. Information about pathologic radial margin status was not reliably provided & not
used in determination of protocol eligibility.
Critical caveat :related to the method of determining the tumor volume to guide
radiation therapy planning.
clip placement :in only 18 (19%) of 94 patients.
Preop. radiologic imaging (ie, barium enema or abdominal/pelvic CT): 45 patients (48%).
For 17 patients (18%), the tumor volume defined by operative notes
6/94 eligible patients assigned to receive chemo-RT refused RT but all included in
primary analysis of chemo-RT arm results
Caveats

46. Results
 median duration of follow-up of living patients was 6.6 years
 reduced statistical power to detect differences between the groups.
 No difference in OS or DFS was seen between the two groups.

47. Grade III or IV hematologic toxicity was higher in patients receiving radiation therapy
no significant difference in non hematologic toxicity.

48. Interpretation of study results was handicapped by
 decreased statistical power
 high ineligibility rates,
 lack of appropriate target volume definition for Rtplanning
No definitive conclusion

49. Technique:
• Bowel preparation
• Positioning:
Supine:
Prone:
lateral decubitus:
• Immobilization:
• Contrast: oral& iv
Oral contrast aids in delineating small-bowel, may be useful to compare films in decubitus & supine
positions to determine bowel shift
• Simulation- Conventional/CT
• CT based planning preferred:facilitate defining the tumor bed, beam orientation, and estimating the
volume of small bowel,kidney included within treatment fields

50. Target volume delineation
• TUMOR BED/TARGET
• Involved segment of colon and, when present, the adjacent structures to which it was adherent or
invading
• If adherent to partially resected organ→ whole organ has to be treated if within tolerance
• If adherent to structure (pelvic side wall, psoas, diaphragm) → 3-5 cm margins beyond area of
adherence
• Surgical clips aid in the identification of high-risk areas (i.e., positive margins) to assist in target
delineation
• The nodal basins in the mesentery beyond surgical margins are usually not treated .However the
final inclusion of local & regional nodal group is based on operative & pathologic findings.
• MARGINS:
• Tumor bed covered with a 4- to 5-cm margin proximally and distally and with a 3- to 4-cm margin
medially and laterally to cover areas of potential residual disease

51. FIELD RRANGEMENT
• Field arrangement will vary, depending on the site of the primary disease, as
well as on areas judged to be at high risk for local recurrence
• parallel opposed or other multifield techniques are used to treat target & spare
OAR: small bowel, kidney, liver, S.C

52. Postoperative AP-PA Irradiation Fields Of Extra pelvic Colon Cancer
(Tumor Bed And Nodal Regions).
Para-aortic nodes may be at risk, due to tumor
adherence to posterior abdominal wall with
descending colon cancer.
External and common iliac nodes may be
at risk, from a proximal ceacal/ascending
colon cancer

53. Dose prescription
• total dose depends on the amount of suspected residual disease and
tolerance constraints of surrounding normal tissue.
• initial dose of 45 Gy/25 # at 1.8/# delivered through larger fields to
primary tumor and at-risk tissues followed by reduced boost fields.
• For patients with T4 tumors, the general goal is to treat the tumor bed
to a total dose of 50.4-54Gy
• Any treatment beyond 50 Gy generally mandates exclusion of all
small bowel from the field

54. Critical normal (dose limiting) tissues
• Small intestine: 45-50 Gy
• Liver : 2/3rd of liver should get <30 Gy
• Kidneys: 2/3rd of one kidney should get <20 Gy
• Spinal cord: max dose to spinal cord< 50 Gy

55. Surveillance for colon cancer
History, physical examination & S.CEA:
every 3–6 month for 2 y, then every 6 month for a total of 5 yr
 Colonoscopy:
In 1st yr:
Abnormal repeat in one yr.
Normal: repeat in 3rd yr then every 5 yrs
If it was not done before:
3-6 months post surgery.
 CT scan chest & abdomen:
Annually for pts. with high risk for recurrence(eg. LVI/PNI ,poorly
differentiated tumors
NCCN 2015

56. Treatment Options for Metastatic Colon Cancer (Stage IV)
with synchronous liver only or lung only metastases
1. For resectable lesions
 Colectomy with synchronous resection of liver or lung metastases followed by adjuvant
chemotherapy with FOLFOX or CapeOx
 Neoadjuvant CT to increase curative resection rates
2. For unresectable lesions
 Treated with chemotherapy and evaluated every 2 months to assess resectability of liver and/or
lung metastases,colon resection if risk of obstruction or significant bleeding.
 Combination chemotherapy for 2-3 months followed by chemo-radiation with 5-FU or
capecitabine and then resection of metastases and primary
3. For patients that are able to undergo resection of metastatic disease
 6 months of adjuvant therapy with an active regimen for advanced disease, observation, or
shortened course of palliative chemotherapy

57. NEOADJUVANT CHEMOTHERAPY
i. FOLFIRI, CapeOx, or FOLFOX ± bevacizumab
ii. FOLFIRI or FOLFOX + panitumumab if KRAS wild type (WT)
iii. FOLFIRI + cetuximab if KRAS WT
ADJUVANT CHEMOTHERAPY
Adjuvant First-Line Therapy Adjuvant Second-Line Therapy
Good Performance Status
• FOLFOX with or without Bevacizumab.
• FOLFIRI with or without Bevacizumab.
• 5-FU + Leucovrin with bevacizumab
If first line Irinotecan
• FOLFOX ±Bevacizumab.
• Irinotecan ±Cetuximab.
• Capecitabine or 5-FU + Leucovorin
Poor Performance Status
• Capecitabine or 5-FU + Leucovorin ±Bevacizumab.
If first line Oxaliplatin
• FOLFIRI ± Bevacizumab.
• Irinotecan ±Cetuximab.
CHEMOTHERAPY OPTIONS

58. Pts. with unresectable mCRC treated with BSC have poor prognosis( median OS= 5 months).
In contrast, pts. who receive CT have been shown to have a median OS of ≈ 2 yrs.
Metastatic colon cancer: impact of chemotherapy

59. Chemotherapy in metastatic colon cancer

61. Targeted agents

62. Cetuximab
• Cetuximab is monoclonal antibody against the epidermal growth factor receptor (EGFR).
• Indicated in KRAS wild type ,EGFR expressing colon cancer
• can be added to either FOLFIRI or FOLFOX as first-line treatment of metastatic colorectal cancer
Panitumumab
• Panitumumab indicated in wild type KRAS metastatic colorectal cancer
• The U.S. Food and Drug Administration approved panitumumab for use in patients with metastatic colorectal
cancer refractory to FOLFIRI chemotherapy
• All patients with mCRC should have tumor tissue genotyped for RAS mutations performed only in certified
laboratories
• The testing can be performed on the primary colorectal cancers and/or the metastasis
Patients with any known KRAS mutation should not be treated with either cetuximab or panitumumab

63. Bevacizumab
• monoclonal antibody that binds to vascular endothelial growth factor.
• can be added to either FOLFIRI or FOLFOX as first-line & second line treatment of
metastatic colorectal cancer
Aflibercept
• Aflibercept is anti-VEGF molecule
• evaluated as a component of second-line therapy in patients with metastatic colorectal
cancer
• use of FOLFIRI plus aflibercept is an acceptable second-line regimen for patients
previously treated with FOLFOX-based chemotherapy

64. Regorafenib
• Regorafenib is an inhibitor of multiple tyrosine kinase pathways including VEGF,
PDGF,FGFR,B-Raf, RET,KIT
• Indicated in metastatic colon cancer progressed to 5FU,oxaliplatin irinotecan &
bevacizumab, aflibercept, cetuximab & panitumumab based chemotherapy
• In September 2012, the FDA granted approval for the use of regorafenib in
patients who had progressed on prior therapy.

65. Thank you